| Parkinson’s disease(PD)is the second most common and fastest growing of neurodegenerative disorders.The increase of PD prevalence rate in China is approximately six times the world`s average in the past two decades,ranking NO.1around the globe.Parkinson’s disease is a neurodegenerative disease with prominent death of dopaminergic neurons in the substantia nigra pars compacta(SNpc).The resultant dopamine deficiency within the basal ganglia(BG)leads to a movement disorder characterized by classical parkinsonian motor symptoms including bradykinesia/akinesia,muscular rigidity,rest tremor,and postural and gait impairment.Since the introduction of dopaminergic replacement therapy,levodopa provides the greatest symptomatic benefit,but long-term use is associated with motor complications and reduced efficacy.Then deep brain stimulation(DBS)becomes another important surgical option.DBS is a method of electrical stimulation of specific brain regions by implanting electrodes.It can improve the motor symptoms of PD patients,but the mechanism is still unclear.In recent years,it has been recognized that the pathogenesis of PD is not only related to the significant death of dopaminergic neurons in SNpc and the resulting lack of dopamine.Neurotransmitters other than dopamine and nervous systems outside BG,such as the degeneration of cholinergic neurons in the pedunculopontine nucleus(PPN)and the changes of cerebellar circuits are also related to PD pathogenesis.Zona incerta(ZI)is a heterogeneous subthalamic region connecting with many brain areas.In rodents,the ZI can be divided into four major sectors based on cytoarchitecture,namely a rostral sector(ZIr),a dorsal sector(ZId),a ventral sector(ZIv)and a caudal sector(ZIc).Early pharmacological studies have suggested the involvement of ZI in various functions such as visceral activities,arousal,attention,and locomotion.We noticed Plaha et al.reported that resting tremor in the 4–6 Hz range could be readily induced following low frequency DBS of the ZIc in non-tremor dominant PD patients and high frequency DBS of the ZIc improved contralateral motor scores in patients with medically refractory PD,indicating involvement of ZIc in parkinsonian motor symptoms.However,whether and how ZIc participated in the regulation of parkinsonian motor symptoms remained unclear.To answer the above questions,first,we used optogenetics to specifically activate subgroups of ZIc neurons and found that activation of ZIc glutamatergic neurons,but not GABAergic or cholinergic neurons,induced light-locked parkinsonian motor symptoms including ipsiversive rotations,impaired rearing,bradykinesia/akinesia and impaired motor coordination.Next,by injection of 6-hydroxydopamine in the dorsomedial striatum combined with the fiber photometry system,we found that the activity of this group of neurons is abnormally higher in dopamine-depleted mice.We further found that photo-inhibition of their activity ameliorates the motor deficits.Then,we used viral tracing,slice electrophysiology,combining optogentics with fiber photometry and demonstrated that caudal zona incerta v Glut2~+neurons has monosynaptic glutamatergic projection to the common basal ganglia output substantia nigra pars reticulate(SNpr).Moreover,photo-activation of the incerta-nigral circuitry also induced parkinsonian motor symptoms.Together,our findings provide for the first time a direct and detailed link between ZIc glutamatergic neuronal transmission and parkinsonian motor symptoms,which helps to better understand the mechanisms of PD and support ZIc and its glutamatergic transmission as an important potential therapeutic target in PD treatment. |
PDF Full Text Request